Mortality in generalized pustular psoriasis: A population-based national register study
Authors: Oskar Ericson, Sofia Löfvendahl, Jenny M. Norlin, Harald Gyllensvärd, Marcus Schmitt-Egenolf
Journal: Journal of the American Academy of Dermatology (2023)

To the Editor: Generalized pustular psoriasis (GPP) (prevalence, 1.8-124/million people1Prinz J.C. Choon S.E. Griffiths C.E.M. et al.Prevalence, comorbidities and mortality of generalized pustular psoriasis: a literature review.J Eur Acad Dermatol Venereol. 2023; 37: 256-273https://doi.org/10.1111/jdv.18720Crossref PubMed Scopus (5) Google Scholar,2Löfvendahl S. Norlin J.M. Schmitt-Egenolf M. Prevalence and incidence of generalized pustular psoriasis in Sweden: a population-based register study.Br J Dermatol. 2022; 186: 970-976https://doi.org/10.1111/bjd.20966Crossref PubMed Scopus (15) Google Scholar) is a severe form of pustular psoriasis characterized by acute flares with systemic inflammation.3Umezawa Y. Ozawa A. Kawasima T. et al.Therapeutic guidelines for the treatment of generalized pustular psoriasis (GPP) based on a proposed classification of disease severity.Arch Dermatol Res. 2003; 295: S43-S54https://doi.org/10.1007/s00403-002-0371-6Crossref PubMed Scopus (116) Google Scholar GPP is associated with several comorbidities,1Prinz J.C. Choon S.E. Griffiths C.E.M. et al.Prevalence, comorbidities and mortality of generalized pustular psoriasis: a literature review.J Eur Acad Dermatol Venereol. 2023; 37: 256-273https://doi.org/10.1111/jdv.18720Crossref PubMed Scopus (5) Google Scholar,4Löfvendahl S. Norlin J.M. Schmitt-Egenolf M. Comorbidities in patients with generalized pustular psoriasis: a nationwide population-based register study.J Am Acad Dermatol. 2023; 88: 736-738https://doi.org/10.1016/j.jaad.2022.09.049Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar and ∼50% of patients with GPP have concomitant psoriasis vulgaris (PV).1Prinz J.C. Choon S.E. Griffiths C.E.M. et al.Prevalence, comorbidities and mortality of generalized pustular psoriasis: a literature review.J Eur Acad Dermatol Venereol. 2023; 37: 256-273https://doi.org/10.1111/jdv.18720Crossref PubMed Scopus (5) Google Scholar,4Löfvendahl S. Norlin J.M. Schmitt-Egenolf M. Comorbidities in patients with generalized pustular psoriasis: a nationwide population-based register study.J Am Acad Dermatol. 2023; 88: 736-738https://doi.org/10.1016/j.jaad.2022.09.049Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar We have assessed mortality and cause of death in GPP compared with the general population (GP) and patients with PV. From the Swedish National Patient Register, we identified 1093 physician-diagnosed patients with GPP using a criterion of 1 primary or secondary GPP diagnosis (International Classification of Diseases, 10th revision, code L40.1) in 2004-2015. These were matched (1:5) to controls from the GP and (1:3) to controls with PV (and no GPP or palmoplantar pustulosis), on the basis of sex and age (flowcharts; Supplement 1, available via Mendeley at https://data.mendeley.com/datasets/5tt3kgr9kt/1). Individuals deceased between 2004 and 2020 were identified in the Swedish Cause of Death Register. Survival was compared between groups using Kaplan-Meier curves. Age-stratified hazard ratios (HRs) for all-cause mortality were determined by Cox regression models. In subgroup analysis, we limited analyses to patients with ≥2 GPP diagnoses (a stricter GPP criterion) given at different occasions during the study period and matched controls. In the final GPP cohort (n = 1022), 44% had ≥2 GPP diagnoses and 54% had concomitant PV. The GPP cohort had relatively more deaths over the study period and ∼50% higher mortality rate compared with both control populations (Table I and Supplement 2, available via Mendeley at https://data.mendeley.com/datasets/5tt3kgr9kt/1). Kaplan-Meier survival curves for the GPP cohort (Fig 1 and Supplement 3, available via Mendeley at https://data.mendeley.com/datasets/5tt3kgr9kt/1) showed a drop in survival immediately after diagnosis, which may be due to GPP life-threatening complication, triggered by factors such as infections, drugs, or hypocalcemia.3Umezawa Y. Ozawa A. Kawasima T. et al.Therapeutic guidelines for the treatment of generalized pustular psoriasis (GPP) based on a proposed classification of disease severity.Arch Dermatol Res. 2003; 295: S43-S54https://doi.org/10.1007/s00403-002-0371-6Crossref PubMed Scopus (116) Google Scholar Thereafter, survival for GPP decreased steadily over the study period and was consistently lower than survival curves for the control groups. The mortality rate was higher in the GPP cohort (33/1000 person-years) compared with both GP and PV control populations (21 and 22/1000 person-years), with higher risks (HRs > 1.5) across all age groups. The highest relative risks (HRs > 2) were observed for the younger age groups. However, the absolute death risk was low in these groups (Table I).Table IBaseline characteristics and mortality outcomes (overall and by age at diagnosis) for the GPP cohort and the matched control groupsGPP cohort n = 1022Matched control groupsGeneral population∗Matched on year of birth, sex, and residential area. n = 4842Psoriasis vulgaris†Matched on year of birth, sex, and index year (ie, year of first PPP or PV diagnosis). n = 3048Women, n (%)631 (61.7)3015 (62.3)1886 (61.9)Patients with at least 2 GPP diagnoses (given at different occasions) 2004-2015, n (%)452 (44.2)N/AN/APatients with a psoriasis vulgaris diagnosis‡L40.0 or L40.9 as primary diagnosis. 2004-2015, n (%)555 (54.3)N/AN/AAge at diagnosis, mean (SD)All58.4 (16.6)58.1 (16.5)58.3 (16.5)Men58.0 (16.0)57.6 (16.0)57.8 (16.0)Women58.6 (16.9)58.3 (16.8)58.6 (16.9)Age (intervals) at diagnosis, n (%)18-44211 (20.7)1015 (21.0)633 (20.8)45-64424 (41.5)2038 (42.1)1267 (41.6)65-79284 (27.8)1331 (27.5)845 (27.7)≥80103 (10.1)458 (9.5)303 (9.9)Follow-up time in years (overall and across age at diagnosis intervals), mean (SD)Overall9.3 (4.6)10.0 (4.3)10.1 (4.1)18-4411.3 (3.9)11.2 (3.9)11.5 (3.6)45-6410.4 (4.3)11.0 (4.1)11.1 (3.8)65-798.1 (4.2)8.9 (4.1)9.0 (3.8)≥804.2 (3.5)5.8 (3.7)6.4 (3.6)No. of deaths during follow-up, n (%)Overall315 (30.8)1027 (21.2)679 (22.2)18-447 (0.7)9 (0.2)6 (0.2)45-6481 (7.9)198 (4.1)145 (4.8)65-79135 (13.2)463 (9.6)291 (9.5)≥8092 (9.0)357 (7.4)237 (7.8)Person-years at risk§The total sum of the number of years that each member of a study population has been under observation.Overall955048,23630,92618-44238611,362730245-64441522,33814,05965-79231411,8617622≥8043526751943Mortality rate (per 1000 person-years)Overall33.021.322.018-442.90.80.845-6418.38.910.365-7958.339.038.2≥80211.3133.5122.0Hazard ratios for all-cause mortality in GPP vs general population controls, (CI); (P value)Overall1.81 (1.58-2.08); (p < .001)18-443.49 (1.30-9.42); (P = .013)45-642.07 (1.58-2.70); (P < .001)65-791.61 (1.31-1.97); (P < .001)≥801.88 (1.43-2.46; (P < .001)Hazard ratios for all-cause mortality in GPP vs psoriasis vulgaris controls, (CI); (P value)Overall1.90 (1.63-2.21); (P < .001)18-443.50 (1.18-10.41); (P = .024)45-642.03 (1.52-2.71); (P < .001)65-791.66 (1.32-2.09); (P < .001)≥802.14 (1.58-2.90); (P < .001)GPP, Generalized pustular psoriasis (L40.1 as primary or secondary diagnosis); N/A, not applicable; PPP, palmoplantar pustulosis; PV, psoriasis vulgaris.∗ Matched on year of birth, sex, and residential area.† Matched on year of birth, sex, and index year (ie, year of first PPP or PV diagnosis).‡ L40.0 or L40.9 as primary diagnosis.§ The total sum of the number of years that each member of a study population has been under observation. Open table in a new tab GPP, Generalized pustular psoriasis (L40.1 as primary or secondary diagnosis); N/A, not applicable; PPP, palmoplantar pustulosis; PV, psoriasis vulgaris. The leading cause of death, grouped by International Classification of Diseases chapters, was diseases of the circulatory system. The GPP cohort had more deaths from circulatory, respiratory, and digestive diseases compared with GP controls (P < .001) and from digestive system compared with PV controls (P = .011) (Supplement 4, available via Mendeley at https://data.mendeley.com/datasets/5tt3kgr9kt/1). When limiting the analysis to patients with at least 2 codes for GPP (Supplement 5, available via Mendeley at https://data.mendeley.com/datasets/5tt3kgr9kt/1), we found a higher GPP mortality rate (overall 39.2/1000 person-years) and higher HRs (overall 2.13 compared with both control groups), suggesting that the stricter criterion resulted in selection of patients with more severe disease. The GPP mortality was in the higher range compared with small clinical studies (mortality rate range, 0-33/1000 person-years)1Prinz J.C. Choon S.E. Griffiths C.E.M. et al.Prevalence, comorbidities and mortality of generalized pustular psoriasis: a literature review.J Eur Acad Dermatol Venereol. 2023; 37: 256-273https://doi.org/10.1111/jdv.18720Crossref PubMed Scopus (5) Google Scholar and a large Japanese study (n = 1516) on hospitalized patients with GPP (4.2% died over a 10-year period).5Miyachi H. Konishi T. Kumazawa R. et al.Treatments and outcomes of generalized pustular psoriasis: a cohort of 1516 patients in a nationwide inpatient database in Japan.J Am Acad Dermatol. 2022; 86: 1266-1274https://doi.org/10.1016/j.jaad.2021.06.008Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Limitations include potential GPP misclassification due to lack of standard case definition. Strengths of our study include the large national and representative GPP cohort, the longitudinal design, and the comparison with 2 control populations. Dr Schmitt-Egenolf is responsible for dermatology in the project management for the national guidelines for psoriasis at the Swedish Board of Health and Welfare. Drs Norlin and Löfvendahl have been involved in the health economic analyses of the national guidelines for psoriasis at the Swedish Board of Health and Welfare. Mr Gyllensvärd is an employee of Boehringer Ingelheim AB, Sweden. Drs Schmitt-Egenolf, Norlin, and Löfvendahl and Mr Gyllensvärd have no conflicts of interest to declare.